Development of novel 4‐arylpyridin‐2‐one and 6‐arylpyrimidin‐4‐one positive allosteric modulators of the M1 muscarinic acetylcholine receptor

Scammells, P. J. et al. (2021) Development of novel 4‐arylpyridin‐2‐one and 6‐arylpyrimidin‐4‐one positive allosteric modulators of the M1 muscarinic acetylcholine receptor. ChemMedChem, 16(1), pp. 216-233. (doi: 10.1002/cmdc.202000540) (PMID:32851779)

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Abstract

This study investigated the structure‐activity relationships of 4‐phenylpyridin‐2‐one and 6‐phenylpyrimidin‐4‐one muscarinic M1 acetylcholine receptor (M1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 (1) and MIPS1780 (2). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP1 accumulation and β‐arrestin 2 recruitment assays demonstrated that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM 7f is a potential lead candidate for further development of peripherally‐restricted M1 PAMs, due to its lower blood‐brain‐barrier (BBB) permeability and improved exposure in the periphery compared to lead 2.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Khajehali, Dr Elham and Tobin, Andrew
Authors: Scammells, P. J., Jörg, M., Khajehali, E., van der Westhuizen, E. T., Choy, K.H. C., Shackleford, D., Tobin, A. B., Sexton, P. M., Valant, C., Capuano, B., and Christopoulos, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:ChemMedChem
Publisher:Wiley
ISSN:1860-7179
ISSN (Online):1860-7187
Published Online:26 August 2020
Copyright Holders:Copyright © 2020 Wiley-VCH GmbH
First Published:First published in ChemMedChem 16(1): 216-233
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173304Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZMCSB - Molecular Pharmacology